Our long term objective is to understand why tamoxifen, an antiestrogen used in breast cancer treatment, in some circumstances behaves as an estrogen agonist and stimulates gene expression. Tamoxifen has tissue specific estrogen-like effects when estrogen receptor alpha (ERalpha) activates target genes regulated by AP-1 sites. Tamoxifen working through the newly discovered estrogen receptor beta (ERbeta) has even more powerful and tissue independent effects on target genes with AP-1 sites. We want to understand the mechanisms whereby ERs enhance the activity of such AP-1 target genes, why ERbeta is a super-enhancer, and the physiological role of such enhancement. These are our aims: Aim 1. Investigate the hypothesis that both estrogen-bound and tamoxifen-bound ERs stimulate transcription from promoters regulated through AP-1 sites by enhancing the activity of the coactivator complex consisting of CBP and p160 proteins that Jun and Fos have recruited to the site. Aim 2. Investigate the potential mechanisms whereby (A) estradiol-ERalpha and (B) tamoxifen-ERalpha enhance the activity of the CBP:p160 complex recruited by Jun/Fos. Aim 3. Investigate why tamoxifen allows ERbeta, unlike ERalpha, to stimulate gene expression at AP-1 in breast cancer cells, and determine whether this action of ERbeta plays a role in the phenomenon of tamoxifen resistance during breast cancer progression. Aim 4. Determine the physiological role of ER activation of AP-1 target genes in uterine and mammary development by studying mice in which we have replaced the gene for the wild type ERalpha with altered versions that are selectively defective or superactive at AP-1 sites depending on the ligand. If successful, these studies will lead to a understanding of the molecular mechanisms and physiological roles of ER action at AP-1 sites, neither of which are currently known. These studies will also have profound consequences for the development of a new generation of antiestrogens for breast cancer treatment and prevention.